Design space approach in the development of esculetin nanocrystals by a small-scale wet-bead milling process

Esculetin, a natural coumarin derived from herbs, has shown different potential pharmacological activities. However, the poor aqueous solubility of esculetin may limit its therapeutic efficacy. Nanocrystal is a promising dosage form to overcome this drawback by enhancing drug saturation solubility. Hence, a laboratory-scale wet-bead milling approach was employed to develop an esculetin nanocrystal formulation. Povacoat™ was selected as a stabilizer after screening different surfactants and polymers. Design of experiments was applied to identify and understand the relationship between process parameters and formulation compositions at the stage of formulation optimization. Furthermore, the optimized formulation was solidified using two different approaches (spray-drying and freeze-drying) and characterized by dynamic light scattering, laser diffraction, transmission electron microscopy, scanning electron microscopy, thermal analysis, and X-ray powder diffraction. An esculetin-Povacoat™ nanocrystal formulation that maintained a 200 nm particle size for 180 days was successfully obtained with specific critical process parameters and formulation composition within the design space. [Display omitted]